The mechanisms of aging (i.e., progressive decline in the capacity to survive and reproduce with age) have perplexed society and the scientific community for centuries. There are two currently prevailing theories, one that aging results from a genetically preprogrammed evolutionary path and the other that aging is a normal consequence of existence during which cellular and molecular damage accumulates. This damage would include oxidative damage induced by free radicals, defective mitochondria, somatic mutations, progressive shortening of telomeres, programmed cell death, proliferation of damaged cells, etc. (Semsei I. (2000) On the nature of aging. Mech Aging Dev 117:93-108).
It has been shown, in organisms like yeast and mice, that caloric reduction exerts a decisive positive impact on lifespan extension (Sohal, R S, Weindruch, R (1998) Oxidative stress, caloric restriction, and aging. Science 273:59-63; Finch, C E, Revkun, G. (2001) The genetics of aging. Annu. Rev. Genom. Hum. Genet. 2:435-462). Recent studies have shown that caloric restriction would also be effective in primates, including humans (Roth, G S, Lasnikov, V, Lesnikov, M, Ingram, D K, Land, M A (2001) Dietary caloric restriction prevents the age-related decline in plasma melatonin levels of rhesus monkeys. J Clin Endocrinol Metab. 86: 3292-5; Roth G S, Lane M A, Ingramn D K, Mattison J A, Elahi D, Tobin J D, Muller D, Metter E J (2002) Biomarkers of caloric restriction may predict longevity in humans. Science. 297: 811-813; Walford R L, Mock D, Verdery R, MacCallum T. (2002) Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humane restricted for a 2-year period. J Gerontol A Biol Sci Med Sci 57: 211-24). Unfortunately, it is probable that the majority of humans are not capable of following the strict diet required to benefit from this discovery.
For several years, many research groups have been dedicated to identifying the genes and signalling pathways involved in the aging process. The studies reported here are conducted in numerous organisms, including yeast Saccharomyces cerevisiae, worm Caenorhabditis elegans and fly Drosophila melanogaster (Fontana et al., 2010), and permitted identifying a growing list of genes. Many of them are involved in hormone signalling and are conserved in a large variety of eukaryotic organisms. It has become clear that, at least for lower species, the pathways responsible for development and growth at the start of life retain a lifelong influence and even partially condition its duration. These studies have also indirectly shown the importance of metabolic capacity and stress resistance for evaluating the lifespan of a subject.
For example, mutants of the clk-1 gene of Caenorhabditis elegans were involved in reducing the extra-mitochondrial production of reactive oxygen species (Hekimi, S, Guarente, L. (2003) Genetics and the specificity of the aging process. Science 299:1351-1354). WO 98/17823 describes the function of the clk-1 gene in the processes of development and longevity. It particularly claims a method to increase an individual's lifespan by regulation of clk-1 gene expression.
A mutation of the Methuselah gene (which codes for a G-protein coupled receptor) has also been described as capable of increasing the lifespan of Drosophila by around 35% (U.S. Pat. No. 6,303,768).
Telomere shortening is also known as a mechanism responsible for cell aging. In vertebrates, telomerase is a ribonucleoprotein (RNP) reverse transcriptase whose role is to maintain the length of telomeres by addition of telomeric DNA to the end of chromosomes in dividing eukaryotic cells (Kiss, 2002). In humans, a mutation in the H/ACA box of telomerase snoRNA causes a pleiotropic genetic disease, dyskeratosis congenita, whose patients present shorter telomeres (Mitchell et al., 1999; Vulliamy et al., 2001). Despite the efforts of the scientific community to decode the mechanisms of aging and identify new therapeutic targets to delay this process and/or combat its harmful effects, the tools available remain insufficient. The need for tools that permit “aging well”, that is without the diseases and discomforts generally associated with old age, is felt all the more now that medical progress combined with general improvement in life conditions have already permitted the human population, in just a few decades, to increase its life expectancy in a very significant manner.